KR100609371B1 - Crystalline Forms of R-R*,R*-2-4-Fluorophenyl-Beta,Delta-Dihydroxy-5-1-Methylethyl-3-Phenyl-4-PhenylaminoCarbonyl-1H-Pyrrole-1-Heptanoic Acid Calcium Salt 2:1Atorvastatin - Google Patents

Abstract

[R- (), which represents Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII and Form XIX R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl]- The novel crystalline forms of 1H-pyrrole-1-heptanate hemicalcium salt atorvastatin are characterized by their X-ray powder diffraction, solid-state NMR and / or Raman spectroscopy, as well as hyperlipidemia, hypercholesterolemia, Methods for the preparation and pharmaceutical compositions of the above crystalline forms useful as drugs for the treatment of osteoporosis and Alzheimer's disease are described.

Atorvastatin, crystalline form, X-ray powder diffraction, solid-state NMR, Raman spectroscopy

Description

R- (R *, R *)-2- (4-fluorophenyl) -beta, delta-dihydroxy-5- (1-methylethyl) -3-phenyl-4-phenylamino) carbonyl-1H Crystalline Forms of R- (R *, R *)-2- (4-Fluorophenyl) -Beta, Delta-Dihydroxy-5--Pyrrole-1-heptanate Calcium Salt (2: 1) (atorvastatin) (1-Methylethyl) -3-Phenyl-4-Phenylamino) Carbonyl-1H-Pyrrole-1-Heptanoic Acid Calcium Salt (2: 1) (Atorvastatin)}

Chemical name [R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl, useful as a medicament Novel crystalline forms of atorvastatin, known as -4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic hemicalcium salt, methods for their preparation and isolation, these compounds and pharmaceutically acceptable carriers In addition to pharmaceutical compositions comprising, it relates to methods of using said compositions for treating a subject, including human subjects suffering from hyperlipidemia, hypercholesterolemia, osteoporosis and Alzheimer's disease.

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate limiting step in cholesterol biosynthesis. This step is catalyzed with the enzyme HMG-CoA reductase. Statins inhibit the HMG-CoA reductase from catalyzing the transformation. As above, statins are collectively potent lipid lowering agents.

Atorvastatin calcium (described in US Pat. No. 5,273,995, which is incorporated herein by reference), has the current chemical name [R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanate calcium salt (2: 1) trihydrate and is of the formula Commercially available as Lipitor (registered trademark).

Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase. As such, atorvastatin calcium is an effective lipid lowering compound and is thus useful as a hyperlipidemic and / or hypercholesterolemia.

US Patent No. 4,681,893 (incorporated herein by reference) includes trans (±) -5- (4-fluorophenyl) -2- (1-methylethyl) -N, 4-diphenyl-1-[( Certain trans-6- [2- (3- or 4-, including 2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl] -1H-pyrrole-3-carboxamide Carboxamido-substituted-pyrrol-1-yl) alkyl] -4-hydroxy-pyran-2-ones are disclosed.

US Pat. No. 5,273,995 (incorporated herein by reference) includes trans-5- (4-fluorophenyl) -2- (1-methylethyl) -N, 4-diphenyl-1-[(2-tetra [R- (R, which is an enantiomer having the R form of the ring-opening acid of hydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl] -1H-pyrrole-3-carboxamide, ie atorvastatin ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) -carbonyl]- 1H-pyrrole-1-heptanoic acid is disclosed.

US Patent No. 5,003,080; 5,097,045; 5,097,045; 5,103,024; 5,103,024; 5,124,482; 5,124,482; 5,149,837; 5,149,837; 5,155,251; 5,155,251; 5,216,174; 5,216,174; 5,245,047; 5,248,793; 5,248,793; 5,280,126; 5,280,126; 5,397,792; 5,397,792; 5,342,952; 5,342,952; 5,298,627; 5,298,627; 5,446,054; 5,446,054; 5,470,981; 5,470,981; 5,489,690; 5,489,690; 5,489,691; 5,489,691; 5,510,488; US Pat. 5,998,633; 5,998,633; And 6,087,511, which are incorporated herein by reference, disclose various methods and major intermediates for preparing amorphous atorvastatin. Amorphous atorvastatin is inadequate in filtration and drying properties for mass production and must be protected from heat, light, oxygen and moisture.

Crystalline forms of atorvastatin calcium are described in US Pat. Nos. 5,969,156 and 6,121,461 (these documents are incorporated herein by reference).

International Patent Application Publication No. WO 01/36384 discloses a so-called atorvastatin calcium polymorph.

Stable oral formulations of atorvastatin calcium are disclosed in US Pat. Nos. 5,686,104 and 6,126,971.

Atorvastatin is a calcium salt thereof, that is, [R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl- 4-[(phenylamino) carbonyl] -1 H-pyrrole-1-heptanate calcium salt (2: 1). The calcium salt of atorvastatin is preferably calcium salt because atorvastatin can be conveniently formulated for oral administration, for example, in tablets, capsules, lozenges, powders and the like. In addition, there is a need to prepare atorvastatin in pure and crystalline form, which can be formulated to meet exact pharmaceutical requirements and specifications.

In addition, the method for preparing atorvastatin needs to be suitable for mass production. In addition, it is desirable only if the product is in a form that can be easily filtered and easily dried. Finally, it is economically desirable for the product to be stable for extended periods of time without the need for specified storage conditions.

We have surprisingly and unexpectedly discovered new crystalline forms of atorvastatin. Accordingly, the present invention provides atorvastatin in a new crystalline form, showing forms V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII and XIX. The new crystalline form of atorvastatin is purer, more stable, and advantageous to produce than the amorphous product.

Summary of the Invention

Accordingly, the present invention is characterized by the following X-ray powder diffraction pattern expressed for 2θ and relative intensity with relative intensity greater than 10%, measured using CuK _α radiation on a Shimadzu diffractometer. Form V atorvastatin and its hydrates.

In addition, the following X-ray powder diffraction pattern of crystalline Form V atorvastatin expressed in relation to 2θ values was measured on an Inel (capillary) diffractometer.

Further, the present invention relates to crystalline Form V atorvastatin and its hydrates characterized by the following solid-state ¹³ C nuclear magnetic resonance (ssNMR) spectra in which chemical shifts are expressed in parts per million (ppm).

Further, the present invention relates to crystalline Form V atorvastatin and its hydrates characterized by the following Raman spectra whose peaks are expressed in cm ⁻¹ .

In a preferred embodiment in the first aspect of the invention, the crystalline Form V atorvastatin is trihydrate.

In a second aspect, the present invention is characterized by the following X-ray powder diffraction pattern expressed for 2θ and relative intensity with relative intensity greater than 10%, measured using CuK _α radiation on a Schumaz diffractometer. Form VI atorvastatin and its hydrates.

In addition, the X-ray powder diffraction pattern of crystalline Form VI atorvastatin expressed in relation to the 2θ value was measured on an Inel (capillary) diffractometer.

The present invention also relates to crystalline Form VI atorvastatin and its hydrates characterized by the following solid-state ¹³ C nuclear magnetic resonance (ssNMR) spectra in which chemical shifts are expressed in ppm.

In a third aspect, the invention is characterized by the following X-ray powder diffraction pattern expressed for 2θ and relative intensity with relative intensity greater than 10%, measured using CuK _α radiation on a Schwarz diffractometer. Form VII atorvastatin and its hydrates.

In addition, the X-ray powder diffraction pattern of crystalline Form VII atorvastatin expressed in relation to the 2θ value was measured on an Inel (capillary) diffractometer.

The invention also relates to crystalline Form VII atorvastatin and its hydrates characterized by the following solid-state ¹³ C nuclear magnetic resonance spectra in which chemical shifts are expressed in ppm.

In addition, the present invention relates to crystalline Form VII atorvastatin and its hydrates characterized by the following Raman spectrum, the peak of which is expressed in cm ⁻¹ .

In a preferred embodiment of the third aspect of the invention, the crystalline Form VII atorvastatin is a sesqui (1.5) hydrate.

In a fourth aspect, the invention is characterized by the following X-ray powder diffraction pattern expressed for 2θ and relative intensity with relative intensity greater than 10%, measured using CuK _α radiation on a Schwarz diffractometer. Form VIII atorvastatin and its hydrates.

In addition, the X-ray powder diffraction pattern of crystalline Form VIII atorvastatin expressed in relation to the 2θ value was measured on an Inel (capillary) diffractometer.

The invention also relates to crystalline Form VIII atorvastatin and its hydrates characterized by the following solid-state ¹³ C nuclear magnetic resonance spectra in which chemical shifts are expressed in ppm.

In addition, the invention relates to crystalline Form VIII atorvastatin and its hydrates characterized by the following Raman spectrum, in which the peak is expressed in cm ⁻¹ .

In a preferred embodiment of the fourth aspect of the invention, the crystalline form VIII atorvastatin is a dihydrate.

In a fifth aspect, the invention is characterized by the following X-ray powder diffraction pattern expressed for 2θ and relative intensity of greater than 10% relative intensity, measured using CuK _α radiation on a Schwarz diffractometer. Form IX atorvastatin and its hydrates.

In addition, the X-ray powder diffraction pattern of crystalline Form IX atorvastatin expressed in relation to the 2θ value was measured on an Inel (capillary) diffractometer.

In a sixth aspect, the present invention is characterized by the following X-ray powder diffraction pattern expressed for 2θ and relative intensity with relative intensity greater than 10%, measured using CuK _α radiation on a Schwarz diffractometer. Crystalline Form X atorvastatin and its hydrates.

In addition, the X-ray powder diffraction pattern of crystalline Form X atorvastatin expressed in relation to the 2θ value was measured on an Inel (capillary) diffractometer.

The invention also relates to crystalline Form X atorvastatin and its hydrates characterized by the following solid-state ¹³ C nuclear magnetic resonance spectra in which chemical shifts are expressed in ppm.

Further, the present invention relates to crystalline Form X atorvastatin and its hydrates characterized by the following Raman spectra whose peaks are expressed in cm ⁻¹ .

In a preferred embodiment of the sixth aspect of the invention, the crystalline Form X atorvastatin is trihydrate.

In a seventh aspect, the invention is characterized by the following X-ray powder diffraction pattern expressed for 2θ and relative intensity of relative intensity greater than 10%, measured using CuK _α radiation on a Schwarz diffractometer. Form XI atorvastatin and its hydrates.

In an eighth aspect, the present invention is characterized by the following X-ray powder diffraction pattern expressed for 2θ and relative intensity of greater than 10% relative intensity, measured using CuK _α radiation on a Schwarz diffractometer. Form XII atorvastatin and its hydrates.

In addition, the X-ray powder diffraction pattern of the crystalline form XII atorvastatin expressed in relation to the 2θ value was measured on an Inel (capillary) diffractometer.

In addition, the present invention relates to crystalline Form XII atorvastatin and its hydrates characterized by the following Raman spectrum, the peak of which is expressed in cm ⁻¹ .

In a ninth aspect, the invention is characterized by the following X-ray powder diffraction pattern expressed for 2θ and relative intensity of greater than 10% relative intensity, measured using CuK _α radiation on a Schwarz diffractometer. Form XIII atorvastatin and its hydrates.

In a tenth aspect, the present invention provides the following X-ray powder diffraction pattern expressed for 2θ and relative intensity with relative intensity greater than 10%, measured using CuK _α radiation on a Bruker D5000 diffractometer. Characterized in crystalline form XIV atorvastatin and its hydrate.

In an eleventh aspect, the invention features the following X-ray powder diffraction pattern expressed for 2θ and relative intensity greater than 10%, as measured using CuK _α radiation on a Bruker D5000 diffractometer. To crystalline form XV atorvastatin and its hydrates.

In a twelfth aspect, the invention is characterized by the following X-ray powder diffraction pattern expressed for 2θ and relative intensity greater than 10%, as measured using CuK _α radiation on a Bruker D5000 diffractometer. Crystalline form XVI atorvastatin and its hydrates.

In addition, the X-ray powder diffraction pattern of the following crystalline form XVI atorvastatin, expressed in terms of 2θ values, was measured using CuK _α radiation on a Schwarz diffractometer.

In addition, the X-ray powder diffraction pattern of the crystalline form XVI atorvastatin expressed in relation to the 2θ value was measured on an Inel (capillary) diffractometer.

In a thirteenth aspect, the invention features the following X-ray powder diffraction pattern expressed for 2θ and relative intensity greater than 10%, measured using CuK _α radiation on a Bruker D5000 diffractometer Crystalline form XVII atorvastatin and its hydrates.

In a fourteenth aspect, the present invention is characterized by the following X-ray powder diffraction pattern expressed for 2θ and relative intensity of greater than 10% relative intensity, measured using CuK _α radiation on a Bruker D5000 diffractometer. Crystalline form XVIII atorvastatin and its hydrates.

In addition, the following X-ray powder diffraction pattern of crystalline form XVIII atorvastatin expressed in terms of 2θ was measured on a Schumaz diffractometer using CuK _α radiation.

In addition, the X-ray powder diffraction pattern of the crystalline form XVIII atorvastatin expressed in relation to the 2θ value was measured on an Inel (capillary) diffractometer.

In a fifteenth aspect, the invention features the following X-ray powder diffraction pattern expressed for 2θ and relative intensity of greater than 10% relative intensity, measured using CuK _α radiation on a Bruker D5000 diffractometer. Crystalline form XIX atorvastatin and its hydrates.

The novel crystalline form of atorvastatin is useful as an inhibitor of HMG-CoA reductase, as well as for treating hyperlipidemia and hypercholesterolemia as well as osteoporosis and Alzheimer's disease.

Still further embodiments of the present invention provide crystalline Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, A pharmaceutical composition for administering form XV, form XVI, form XVII, form XVIII or form XIX atorvastatin in an effective amount. Finally, the present invention relates to Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII or Form A method for producing XIX atorvastatin.

The invention is further described by the following non-limiting examples, which are shown in FIGS. 1 to 35 with the brief description given below.

1

Diffractograms of Form V atorvastatin measured on a Schmatsu XRD-6000 diffractometer.

2

Diffractograms of Form VI atorvastatin as measured on a Schmatsu XRD-6000 diffractometer.

3

Diffractograms of Form VII atorvastatin measured on a Schmatsu XRD-6000 diffractometer.

4

Diffractograms of Form VIII atorvastatin measured on a Schmatsu XRD-6000 diffractometer.

5

Diffractogram of Form IX atorvastatin, measured on a Schmatsu XRD-6000 diffractometer.

6

Diffractograms of Form X atorvastatin as measured on a Schumaz XRD-6000 diffractometer.

7

Diffractograms of Form XI atorvastatin measured on a Schmatsu XRD-6000 diffractometer.

8

Diffractograms of Form XII atorvastatin measured on a Schmatsu XRD-6000 diffractometer.

9

Diffractograms of Form XIII atorvastatin measured on a Schmatsu XRD-6000 diffractometer.

10

Diffractogram of form XIV atorvastatin measured on a Bruker D 5000 diffractometer.

11

Diffractogram of form XV atorvastatin measured on a Bruker D 5000 diffractometer.

Figure 12

Diffractogram of form XVI atorvastatin measured on a Bruker D 5000 diffractometer.

13

Diffractogram of Form XVII atorvastatin measured on a Bruker D 5000 diffractometer.

14

Diffractogram of form XVIII atorvastatin measured on a Bruker D 5000 diffractometer.

Figure 15

Diffractogram of form XIX atorvastatin measured on a Bruker D 5000 diffractometer.

Figure 16

Diffractograms of Form V atorvastatin measured on an Inel XRG-3000 diffractometer.

Figure 17

Diffractograms of Form VI atorvastatin measured on an Inel XRG-3000 diffractometer.

Figure 18

Diffractograms of Form VII atorvastatin measured on an Inel XRG-3000 diffractometer.

Figure 19

Diffractogram of Form VIII atorvastatin measured on an Inel XRG-3000 diffractometer.

Figure 20

Diffractogram of Form IX atorvastatin performed on Inel XRG-3000 diffractometer.

Figure 21

Diffractograms of Form X atorvastatin measured on an Inel XRG-3000 diffractometer.

Figure 22

Diffractogram of Form XII atorvastatin performed on Inel XRG-3000 diffractometer.

Figure 23

Diffractogram of form XVI atorvastatin performed on Inel XRG-3000 diffractometer.

Figure 24

Diffractogram of form XVIII atorvastatin performed on Inel XRG-3000 diffractometer.

Figure 25

Solid-state ¹³ C nuclear magnetic resonance spectra of Form V atorvastatin with a rotating sideband identified by an asterisk.

Figure 26

Solid-state ¹³ C nuclear magnetic resonance spectra of Form VI atorvastatin with a rotating sideband identified by an asterisk.

Figure 27

Solid-state ¹³ C nuclear magnetic resonance spectra of Form VII atorvastatin with a rotating sideband identified by an asterisk.

Figure 28

Solid-state ¹³ C nuclear magnetic resonance spectrum of Form VIII atorvastatin with a rotating sideband identified by an asterisk.

Figure 29

Solid-state ¹³ C nuclear magnetic resonance spectrum of Form X atorvastatin.

Figure 30

Raman spectrum of form V.

Figure 31

Raman spectrum of form VI.

Figure 32

Raman spectrum of Form VII.

Figure 33

Raman spectrum of form VIII.

Figure 34

Raman spectrum of Form X.

Figure 35

Raman spectrum of form XII.

Crystalline Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVII, Form XVIII and Form XIX atorvastatin -Line powder diffraction patterns, their solid-state nuclear magnetic resonance spectra (NMR) and / or their Raman spectra.

X-ray powder diffraction

Forms V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII and XIX

Forms V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII or XIX atorvastatin were characterized by their X-ray powder diffraction pattern. For example, the X-ray diffraction pattern of Form V, VI, VII, VIII, IX, X, XI, XII or Form XIII atorvastatin was measured using CuKα radiation on a Shimatsu XRD-6000 X-ray powder diffractometer. . The instrument was equipped with a microfocus X-ray tube. Tube voltage and current were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set to 1 ° and the receiving slits were set to 0.15 mm. Diffraction radiation was detected with a NaI scintillation detector. Theta-2 theta continuous scan at 3 ° / min (0.4 seconds / 0.02 ° steps) at 2θ of 2.5-40 ° was used. Silicon standards were analyzed each day to check instrument alignment. X-ray diffraction patterns of forms XIV, XV, XVI, XVII, XVIII and XIX were measured with a Bruker D5000 diffractometer using copper radiation, fixed slit (1.0, 1.0, 0.6 mm) and Kevex solid state detector It was. Data was collected at 2θ of 3.0 to 40.0 degrees using a step size of 0.04 degrees and a step time of 1.0 seconds. Since Brooker devices are purchased from Siemans, it should be noted that the Bruker D 5000 instrument is essentially the same as the Simans D 5000.

X-ray diffraction patterns of Forms V, VI, VII, VIII, IX, X, XII, XVI and XVIII were also measured on Inel diffractometers. X-ray diffraction analysis was performed on an Inel XRG-3000 diffractometer equipped with a Curved Position Sensitive (CPS) detector having a 2θ range of 120 degrees. Real-time data were collected using CuKα radiation starting at 2θ of approximately 4 ° at a resolution of 2θ of 0.03 °. Tube voltage and current were set to 40 kV and 30 mA, respectively. Samples were packed in thin walled glass capillaries to prepare samples for analysis. Each capillary was mounted on a goniometer head that powers to allow capillary rotation during data acquisition. The instrument's assay was done daily using the silicon reference standard. Inel diffractograms for available forms are shown in the figures without baseline cuts. Calculating the intensity from these diffractograms is a skill in the art and involves using baseline cuts to account for background scattering (eg, scattering from capillaries).

In order to perform X-ray powder diffraction measurements on a Schumaz or Bruker instrument, such as the instrument used for the measurements reported herein, the sample is typically placed in a cavity holder. Sample powder is squeezed with a glass slide or equivalent to ensure random surface and proper sample height. The sample holder is then placed in the (Schmatsu or Bruker) instrument. The source of the X-ray beam was first placed on the sample at a small angle to the face of the holder and moved through an arc that continuously increased the angle between the incident beam and the holder face. Measurement differences with respect to the X-ray powder analysis may include (a) error in sample preparation (eg, sample height), (b) instrument error (eg, flat sample error), (c) calibration error, (d) due to various factors including operating errors (including errors present in peak positioning) and (e) preferred orientation. Test errors and sample height errors often shift all peaks in the same direction and in the same amount. Small differences in sample height on the flat holder cause large shifts in the XRPD peak position. Histological studies have shown that using a Schmatsu XRD-6000 in a typical Bragg-Brentano arrangement, a sample height difference of 1 mm shifts the height peak by 2θ of 1 ° (Chen, et al. , J. Pharmaceutical and Biomedical Analysis, 2001; 26: 63]. The shift can be confirmed from the X-ray diffractogram and can be removed by correction for the shift (applied a systematic correction factor to all peak position values) or by recalibration of the instrument. In contrast, the Innel instrument used herein places the sample in a capillary tube located in the center of the instrument. This minimizes sample height error (a) and favors orientation (e). When using capillaries, the sample position is not achieved manually, so the peak position from the innell measurements is typically more accurate than the peak from a Schumaz or Bruker instrument. As mentioned above, by applying a tissue correction factor, it is possible to calibrate measurements from various machines to match peak positions. In general, this correction factor will match the peak position from Shimatsu and Bruker to Inel, which will be in the 2θ range of 0 to 0.2 degrees.

Table 1 lists the 2θ and relative intensities of all lines in the samples with relative intensities greater than 10% relative to crystalline forms V through XIX atorvastatin. The numbers listed in this table are rounded numbers.

Since only 19 atorvastatin crystalline forms are known, each form can be identified and distinguished from other crystalline forms by different line combinations or pattern combinations with other forms of X-ray powder diffraction.

For example, Table 2 lists the combination of 2θ peaks for Forms V to XIX atorvastatin, i.e., a set of X-ray diffraction lines specific for each form. Forms I to IV atorvastatin are disclosed in US Pat. No. 5,969,156, which includes 6,121,461 in comparison.

Solid State Nuclear Magnetic Resonance (NMR)

Way

Solid-state ¹³ C NMR spectra were obtained on 270 or 360 MHz Tecmag groups. High-power proton pairing and cross-polarization is used for 68 MHz ( ¹³ C frequency) data acquisition with magic-angle rotation using approximately 4.7 and 4.2 kHz or 4.6 and 4.0 kHz, and 4.9 and 4.4 kHz are 91 MHz ( ¹³ C frequency). ) Was used for data acquisition. The magic angle was adjusted using Br signal of KBr by sideband detection. Samples were packed in 7 mm Doty rotors and used for each experiment. Except for Form X, where chemical shifts are arbitrary, chemical shifts are based on external adamantines.

Table 3 shows the solid-state NMR spectra for crystalline forms V, VI, VII, VIII, and X atorvastatin.

Table 4 shows specific solid-state NMR peaks, ie, peaks within ± 1.0 ppm, for Forms V, VI, VII, VIII and X atorvastatin. Forms I to IV atorvastatin are included for comparison.

Raman spectroscopy

Way

Raman spectra were acquired on a Raman aid in contact with a Nicolelet Magna 860 Fourier transform infrared spectrometer. The aid uses neodymium-doped yttrium aluminum garnet (Nd: YAG) laser power with an excitation wavelength of 1064 nm and approximately 0.45 W. The spectrum shows 64 or 128 cavity addition scans taken at 4 cm ⁻¹ resolution. A sample was prepared for analysis by placing a portion in a 5-mm diameter glass tube and placing the tube in a spectrometer. (Wavelength) assay with sulfur and cyclohexane when using the spectrometer.

Table 5 shows the Raman spectra for Forms V, VI, VII, VIII, X and XII atorvastatin.

Table 6 lists the specific Raman peaks of Forms V, VI, VII, VIII, X and XII atorvastatin, ie, only one other form has a peak of ± 4 cm ⁻¹ . For Forms VI and X, the peak combination is unique. Forms I to IV atorvisstatin are included for comparison.

Crystalline forms V to XIX atorvastatin of the present invention may exist in anhydrous forms as well as in hydrated and solvated forms. In general, the hydrated form is equivalent to the non-hydrated form and is intended to be included within the scope of the present invention. Crystalline Form XIV contains about 6 moles of water. Preferably, Form XIV contains 6 moles of water. Crystalline forms V, X and XV atorvastatin contain about 3 moles of water. Preferably, Forms V, X and XV atorvastatin contain 3 moles of water.

Crystalline Form VII contains about 1.5 moles of water. Preferably, Form VII atorvastatin contains 1.5 moles of water. Crystalline Form VIII contains about 2 moles of water. Preferably, Form VIII atorvastatin contains 2 moles of water.

Crystalline forms XVI to XIX may exist as solvates.

Regardless of the amount of hydration and / or solvation, crystalline forms of the atorvastatin of the invention having the same x-ray powder diffractogram, ssNMR or Raman spectrum are within the scope of the invention.

In general, the crystalline form may have advantageous properties. Polymorphs, solvates or hydrates are identified by their crystal structure and properties. The crystal structure can be obtained from X-ray data or close from other data. The property is measured by inspection. The formulas and chemical structures do not describe or suggest crystal structures of any particular polymorph or crystalline hydrate form. No specific crystalline form can be identified from the formula, and no method can be used to identify any particular crystalline solid form or describe its properties from the formula. Chemical compounds can exist in three states-solid, solution and gas-but the crystalline solid form is only in the solid state. Once the chemical compound is dissolved or melted, the crystalline solid form is destroyed and no longer exists (Wells JI, Aulton ME Pharmaceutics. The Science of Dosage Form Design. Reformulation, Aulton ME ed., Churchill Livingstone, 1988; 13 : 237]).

The new crystalline forms of atorvastatin described herein have advantageous properties. Form VII has better chemical stability compared to Form I (described in US Pat. No. 5,969,156). Since the amorphous form of atorvastatin is not chemically stable, this property would be a significant advantage, which would enhance shelf life and extend the expiration date. Form VII can be made from acetone / water, while Form I is made from a more toxic methanol / water system. Form VII is a sesqui (1.5) hydrate and contains less water, meaning that form VII contains more atorvastatin molecules in unit weight and is more potent.

The ability of a substance to form good tablets on a commercial scale is characterized by the physical properties of various drugs, such as Hiestand H. and Smith D., Indices of Tableting Performance, Powder Technology, 1984; 38: 145-159]. This index can be used to identify the form of atorvastatin calcium that performs well in tabletting. One of these indices is the Vulnerability Breakdown Index (BFI) that reflects vulnerability, and ranges from 0 (good-low vulnerability) to 1 (bad-high vulnerability). For example, the BFI value of Form VII is 0.09, while the BFI value of Form I is 0.81. Thus, Form VII is less fragile than Form I. This lower vulnerability indicates that the manufacture of tablets is easier.

Form VIII also has less water than Form I (dihydrate versus trihydrate), so Form VIII contains more atorvastatin molecules per gram.

Form X can be prepared in a less toxic isopropanol (IPA): water system, which is advantageous in that it avoids the more toxic methanol: water system.

Form XII has the highest melting point 210.6. Since the high melting point relates to stability at high temperatures, this means that Form XII is most stable at temperatures near the melting point. High melt forms may be advantageous when processing methods involving high temperatures are used. Form XII can also be prepared from a less toxic tetrahydrofuran (THF): water system.

Form XIV is prepared using a less toxic THF / water system.

The present invention provides a process for the preparation of crystalline forms V to XIX atorvastatin, which comprises crystallizing atorvastatin from a solution in a solvent under the conditions of obtaining crystalline forms V to XIX atorvastatin.

The specific conditions under which crystalline forms V to XIX atorvastatin are formed can be determined experimentally and are only applicable to a few methods that have been found to be suitable in practice.

The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, ie, intravenously, intramuscularly, intradermal, subcutaneous, duodenum or intraperitoneally. In addition, the compounds of the present invention may be administered by inhalation, for example intranasally. In addition, the compounds of the present invention may be administered transdermally. It will be apparent to those skilled in the art that the following dosage forms may comprise a compound of the invention or a corresponding pharmaceutically acceptable salt of the compound of the invention as an active ingredient.

For preparing pharmaceutical compositions from the compounds of the present invention, the pharmaceutically acceptable carrier may be a solid or a liquid. Solid form dosage forms include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances that can also function as diluents, flavors, solvating agents, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.

In powders, the carrier is a finely divided solid in admixture with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

Powders and tablets preferably contain 2 or 10 to about 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melt wax, cocoa butter and the like. The term "formulation" is intended to include formulations of the encapsulating material with the active compound as a carrier which are surrounded by a carrier with or without other carriers to provide the active ingredient associated with the carrier in a capsule. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

For suppository preparation, a low melt wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is stirred therein and dispersed homogeneously. The molten homogeneous mixture is then poured into a mold of convenient size and solidified by cooling.

Liquid form preparations include solutions, suspensions, retention enemas and emulsions such as water or water propylene glycol solutions. For parenteral injection, the liquid formulation may be formulated in a solution of aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickeners as desired.

Aqueous suspensions suitable for oral use can be prepared by suspending the active ingredient in water with viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These formulations may include, in addition to the active ingredient, colorants, flavors, stabilizers, butters, artificial and natural sweeteners, dispersants, thickeners, solvating agents, and the like.

Pharmaceutical formulations are preferably in unit dosage form. In this form, the formulation is subdivided into unit dosages containing appropriate amounts of the active ingredient. The unit dosage form may be a packaged preparation, which may include tablets, capsules, and powders packaged in separate amounts, such as vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, casein or lozenge itself or may be any suitable number of such packaged forms.

The amount of active ingredient in unit dosage formulations can vary or be adjusted from 0.5 mg to 100 mg, preferably 2.5 mg to 80 mg, depending on the particular application and the potency of the active ingredient. If desired, the composition may also contain other compatible therapeutic agents.

In therapeutic use as a hyperlipidemia and / or hypercholesterolemia and as a therapeutic agent for osteoporosis and Alzheimer's disease, the crystalline forms V to XIX atorvastatin used in the pharmaceutical methods of the present invention initially contain about 2.5 mg to about 80 mg per day. It is administered at a dose of. The daily dosage range is preferably about 2.5 mg to about 20 mg. However, the dosage may vary depending on the needs of the patient, the severity of the condition to be treated and the compound used. Suitable dosages for particular conditions are determined by the prior art. Generally, treatment is started with a smaller dose than the optimal dose of the compound. Thereafter, the dosage is increased in small amounts until the optimum effect is achieved under a given environment. For convenience, the total daily dose may be divided and may be administered once during the day if necessary.

Preferred methods of the inventors of the present invention for preparing compounds are described below, but are not limited to these examples.

Example 1

[R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-[(phenylamino) Carbonyl] -1H-pyrrole-1-heptanoic Hemicalcium Salt (Form V to XIX Atorvastatin)

Form V Atorvastatin

Method A

Amorphous atorvastatin calcium (US Pat. No. 5,273,995) was slurried in a mixture of acetonitrile / water (9: 1) to give crystalline Form V atorvastatin.

Method B

Crystalline Form I atorvastatin calcium (US Pat. No. 5,969,156) was slurried overnight at 60 ° C. in a mixture of acetonitrile / water (9: 1), filtered and air dried to yield crystalline Form V atorvastatin.

Method C

Amorphous atorvastatin calcium (US Pat. No. 5,273,995) was stressed under the vapor of acetonitrile / water (9: 1) to give crystalline Form V atorvastatin.

Method D

Acetonitrile was added to a solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in tetrahydrofuran / water (9: 1) and cooled to afford crystalline Form V atorvastatin.

Method E

Acetonitrile was added to a solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in dimethylformamide / water and rapidly evaporated to give crystalline Form V atorvastatin.

Method F

Amorphous atorvastatin calcium (US Pat. No. 5,273,995) was diffused in a vapor of acetonitrile / water (9: 1) to give crystalline Form V atorvastatin.

Crystalline Form V Atorvastatin, mp 171.4 ° C., Trihydrate

Karl Fischer 4.88% (3 mol of water).

Form VI Atorvastatin

Method A

Amorphous atorvastatin calcium (US Pat. No. 5,273,995) was placed in a vapor vessel containing dimethylformamide / water (9: 1) for 20 days to obtain crystalline Form VI atorvastatin.

Method B

A dimethylformamide / water solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) was rapidly evaporated to obtain crystalline Form VI atorvastatin.

Method C

A dimethylformamide / water (saturated) solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) seeded with crystalline Form VI was rapidly evaporated to obtain crystalline Form VI atorvastatin.                 

Crystalline Form VI Atorvastatin, mp 145.9 ° C.

Form VII atorvastatin

Method A

A solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in acetone / water (1: 1) (5.8 mg / mL) was stirred overnight. The solid formed was filtered to give crystalline Form VII atorvastatin.

Method B

A solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in acetone / water (1: 1) was evaporated at 50 ° C. to obtain crystalline Form VII atorvastatin.

Method C

A saturated solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in acetone / water (1: 1) was seeded with crystalline Form VII atorvastatin to obtain crystalline Form VII atorvastatin.

Method D

A saturated solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in acetone / water (1: 1) was rapidly evaporated and seeded in crystalline form VII to give crystalline form VII atorvastatin.

Crystalline Form VII Atorvastatin, mp 195.9 ° C, 1.5 hydrate

Karl Fischer 2.34% (1.5 mol water).                 

Form VIII Atorvastatin

Method A

A solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in dimethylformamide / water (saturated) (9: 1) was seeded into crystalline form VII and evaporated to give crystalline form VIII atorvastatin.

Method B

A solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in dimethylformamide / water (9: 1) was rapidly evaporated to give crystalline form VIII atorvastatin.

Crystalline Form VIII Atorvastatin, mp 151 ° C., Dihydrate

Karl Fischer 2.98% (2 moles of water).

Form IX Atorvastatin

Method A

A solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) (3.4 mg / mL) in acetone / water (6: 4) was evaporated in a rotary evaporator to give crystalline Form IX atorvastatin.

Method B

A solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in acetone / water (6: 4) was filtered, seeded into crystalline Form IX and evaporated in a rotary evaporator to give crystalline Form IX atorvastatin.                 

Method C

A solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in acetone / water (6: 4) was stirred for 0.5 h, filtered and evaporated in a rotary evaporator to concentrate the solution and dried in a vacuum oven to give crystalline form IX atorvastatin. It was.

Form X Atorvastatin

Method A

A slurry of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in isopropanol / water (9: 1) was stirred for several days, filtered and air dried to yield crystalline Form X atorvastatin.

Method B

A slurry of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in isopropanol / water (9: 1) was stirred for 5 days, filtered and air dried to yield crystalline Form X atorvastatin.

Method C

A saturated solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in isopropanol / water (9: 1) was stirred for 2 days, filtered and air dried to yield crystalline Form X atorvastatin.

Crystalline Form X Atorvastatin, mp 180.1 ° C., Trihydrate

Karl Fischer 5.5% (3.5 moles of water).                 

Form XI Atorvastatin

A solution of amorphous atorvastatin calcium (US Pat. No. 5,273,995) in acetonitrile / water (9: 1) was filtered and evaporated slowly to afford crystalline form XI atorvastatin.

Form XII Atorvastatin

Crystalline Form I atorvastatin calcium (US Pat. No. 5,969,156) was slurried in tetrahydrofuran / water (2: 8) at 90 ° C. for 5 days, filtered and air dried to afford crystalline Form XII atorvastatin.

Crystalline Form XII Atorvastatin, mp 210.6 ° C.

Form XIII Atorvastatin

Crystalline Form I atorvastatin calcium (US Pat. No. 5,969,156) was added to 10 mL of 2: 8 water: methanol to leave a solid layer at the bottom of the vial. The slurry was heated at about 70 ° C. for 5 days. The supernatant was removed and the solid was air dried to yield crystalline Form XIII atorvastatin.

Form XIV Atorvastatin

1 g of amorphous atorvastatin calcium (US Pat. No. 5,273,995) was slurried in 45 mL of isopropyl alcohol / 5 mL of water (9: 1) at ambient temperature for 3 weeks. The mixture was filtered and dried at ambient temperature to give crystalline form XIV atorvastatin.

Differential Scanning Calorimetry (DSC) shows melting at about 150 ° C. after a low desolvation phenomenon at about 60 ° C. (peak). Combustion analysis indicates that the compound is a hexahydrate. Thermography ultraviolet spectroscopy (TG-1R) indicates that the compound contains water. Karl Fischer indicates that the compound contains 5.8% water.

Form XV Atorvastatin

1 g of amorphous atorvastatin calcium (US Pat. No. 5,273,995) was slurried in 45 mL acetonitrile / 5 mL water (9: 1) at ambient temperature for 3 weeks. The mixture was filtered and dried at ambient temperature to give crystalline form XV atorvastatin. DSC shows melting at about 165 ° C. after a low desolvation phenomenon at about 78 ° C. (peak). Combustion analysis indicates that the compound is a trihydrate. TG-1R indicates that the compound contains water.

Form XVI Atorvastatin

1 g of amorphous atorvastatin calcium (US Pat. No. 5,273,995) was slurried in 9: 1 acetonitrile / water at room temperature for about 1 day. The mixture was filtered and dried at ambient temperature to yield crystalline form XVI atorvastatin. DSC shows an endotherm with a broad endotherm and a starting temperature of 164 ° C. at a peak temperature of about 72 ° C. The weight loss profile by thermographic analysis (TGA) shows a total weight loss of about 7% at 30 ° C. to 160 ° C. Combustion analysis shows TGA and Karl Fischer analysis (shows 7.1% water) indicates that the compound is a tetrahydrate / acetonitrile solvate.

Form XVII Atorvastatin

0.5 g of amorphous atorvastatin calcium (US Pat. No. 5,273,995) was slurried in 5 mL of 9: 1 dimethylformamide (DMF) / water containing 25 mL of acetonitrile at room temperature for about 2 days. The mixture was filtered and dried at ambient temperature to yield crystalline Form XVII atorvastatin. DSC showed broad multiple endotherms indicating that the compound was a hydrate.

Form XVIII Atorvastatin

0.5 g of crystalline form XVI atorvastatin was dried at room temperature for about 1 day to obtain crystalline form XVIII atorvastatin. DSC showed a broad endotherm at low temperatures, indicating that the compound was a solvate. Karl Fischer analysis showed that the compound contained 4.4% water.

Form XIX Atorvastatin

0.4 g of amorphous atorvastatin calcium (US Pat. No. 5,273,995) was slurried in 4 mL of methyl ethyl ketone at room temperature for 7 days. The mixture was filtered and dried at ambient temperature to give crystalline form XIX atorvastatin. DSC showed melting at about 125 ° C. after a low desolvation phenomenon at about 50 ° C. (peak). TGA analysis indicates that the compound is a solvate that is desolvated at low temperatures.

Claims (15)

Crystalline Form V atorvastatin or a hydrate thereof, wherein the X-ray powder diffraction comprises 2θ values of 4.9 (wide), 6.0, 7.0, 8.0 (wide), 8.6, 9.9, 16.6, 19.0, and 21.1 measured using CuKα radiation. Crystalline Form VI atorvastatin or a hydrate thereof, wherein the X-ray powder diffraction comprises 2θ values of 7.2, 8.3, 11.0, 12.4, 13.8, 16.8, 18.5, 19.7 (wide), 20.9, and 25.0 measured using CuKα radiation. X-ray powder diffraction measured using CuKα radiation, 8.6, 10.2, 12.4 (wide), 12.8 (wide), 17.6, 18.3 (wide), 19.3, 22.2 (wide), 23.4 (wide), 23.8 (wide) And crystalline Form VII atorvastatin or a hydrate thereof comprising a 2θ value of 25.5 (wide). X-ray powder diffraction was measured using CuKα radiation, 7.5, 9.2, 10.0, 12.1, 12.8, 13.8, 15.1, 16.7 (wide), 18.6 (wide), 20.3 (wide), 21.2, 21.9, 22.4, 25.8, Crystalline form VIII atorvastatin or a hydrate thereof, comprising 26.5, 27.4 (wide) and a 2θ value of 30.5. 8.8, 9.4 (wide), 11.2 to 11.7 (wide), 16.7, 17.5 (wide), 19.3 (wide), 21.4 (wide), 22.4 (wide), 23.2 measured using CuKα radiation Crystalline Form IX atorvastatin or a hydrate thereof comprising a 2θ value of (wide) and 29.0 (wide). X-ray powder diffraction measured using CuKα radiation, 4.7, 5.2, 5.8, 6.9, 7.9, 9.2, 9.5, 10.3 (wide), 11.8, 16.1, 16.9, 19.1, 19.8, 21.4, 22.3 (wide), 23.7 (Wide), crystalline Form X atorvastatin or a hydrate thereof comprising a 2θ value of 24.4 and 28.7. X-ray powder diffraction measured at 2θ values 10.8 (wide), 12.0, 13.5, 16.5, 17.6 to 18.0 (wide), 19.7, 22.3, 23.2, 24.4, 25.8, 26.5, 27.3, 28.7, 29.5 measured using CuKα radiation Crystalline form XI atorvastatin or a hydrate thereof, comprising 2θ values of 30.9 (wide), 32.8 (wide), 33.6 (wide), 36.0 (wide), and 38.5 (wide). X-ray powder diffraction measured at 5.4, 7.7, 8.0, 8.6, 8.9, 9.9, 10.4 (wide), 12.5, 13.9 (wide), 16.2, 17.8, 19.4, 20.8, 21.7, 22.4 to 22.6 measured using CuKα radiation. (Wide), crystalline form XII atorvastatin or a hydrate thereof comprising a 2θ value of 24.3, 25.5, 26.2, and 27.1. X-ray powder diffraction measured using CuKα emission, 8.4, 8.9, 15.7 (wide), 16.4 (wide), 17.6 (wide), 18.1 (wide), 19.7 (wide), 20.8 (wide), and 23.8 (wide) Crystalline form XIII atorvastatin or a hydrate thereof comprising a 2θ value of X-ray powder diffraction includes 2θ values of 5.4, 6.7, 7.7, 8.1, 9.0, 16.5 (wide), 17.6 (wide), 18.0 to 18.7 (wide) and 19.5 (wide) measured using CuKα radiation Crystalline form XIV atorvastatin or its hydrate. Crystalline form XV atorvastatin or a X-ray powder diffraction comprising 2θ values of 5.7, 6.1, 6.8, 7.5, 8.1, 8.5, 9.5, 10.5 (wide) and 19.1 to 19.6 (wide) measured using CuKα radiation Luggage. X-ray powder diffraction measured using CuKα radiation, 5.2, 6.4, 7.5, 8.7, 10.5 (wide), 12.0 (wide), 12.7 (wide), 16.7, 18.3 (wide), 19.5, 20.1 to 20.4 (wide ), Crystalline form XVI atorvastatin or a hydrate thereof comprising a 2θ value of 21.2 to 21.9 (wide), 22.9 to 23.3 (wide), and 24.4 to 25.0 (wide). X-ray powder diffraction measured using CuKα radiation, 5.0, 6.1, 7.3, 7.9, 8.5, 9.1, 10.0, 12.1 (wide), 14.8, 16.0 to 16.5 (wide), 17.5 (wide), 19.0 (wide) Crystalline form XVII atorvastatin or a hydrate thereof comprising a 2θ value of 19.5, 20.2 (wide), 21.3, 21.6, and 22.0. Crystalline form XVIII atorvastatin or a hydrate thereof, wherein the X-ray powder diffraction comprises a 2θ value of 8.0, 9.2 (wide), 9.7 (wide), 12.1, 16.6 (wide), and 18.5, measured using CuKα radiation. X-ray powder diffraction measured using CuKα radiation, measured 5.2, 6.3, 7.0, 8.6, 10.5, 11.6 (wide), 12.7 (wide), 14.0, 16.7 (wide), 18.9, 20.8, 23.6 (wide) and 25.5 Crystalline form XIX atorvastatin or its hydrate comprising a 2θ value of (wide).

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